Methods for the production of 3-methylamino-1-(thiene-2-yl)propane-1-ol
The present invention relates to a process for preparing 3-methylamino-1-(thien-2-yl)propan-1-ol of the formula I
and, in particular, to a process for preparing the S-enantiomer I-S.
The S enantiomer of the aminopropanol I of the formula I-S
is an important precursor for synthesizing the antidepressant duloxetine of the formula II
in which B is an n-fold negatively charged inorganic or organic acid radical and HnB is a pharmaceutically tolerated acid.
Methods of the prior art for preparing duloxetine or its corresponding base are elaborate and necessitate the use of chiral reagents or chiral starting compounds.
Thus, EP-B-0273658 describes a method for preparing the corresponding base of duloxetine by reacting 2-acetylthiophene in a Mannich reaction with formaldehyde and dimethylamine, reducing the keto group of the resulting Mannich base to give racemic (S)-3-N,N-dimethylamino-1-(thien-2-yl)propan-1-ol, etherifying the alcohol function with naphthyl fluoride and finally converting the dimethylamino group into a methylamino function. The desired enantiomer of the naphthyl ether is obtained by means of using chiral starting materials or by means of racemate resolution at the step of the end product, for example by way of the salts with optically active acids or by way of chromatography on a chiral stationary phase.
U.S. Pat. No. 5,362,886 describes an analogous method in which S-mandelic acid is added to the racemic propanol which is obtained after reduction of the keto group. The S enantiomer of the alcohol which is obtained in this connection is used in the subsequent reaction steps.
EP-A-0457559 also describes a method which is analogous to that in EP-B-0273658. In this case, the keto group of the Mannich base is reduced using the asymmetric reducing system LAH-Icb (lithium aluminum hydride-[(2R,2S)-(−)-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol]) to give the alcohol in the form of the S enantiomer. Apart from the costs, a disadvantage of this method is the lability of the reducing system LAH-Icb, which is only stable for a few minutes.
In Journal of Labelled Compounds and Radiopharmaceuticals, volume XXXVI, No. 3, pages 213 to 223, W. J. Wheeler and F. Kuo also describe a method for preparing duloxetine. In this method, thiophene-2-carbonyl chloride is reacted, in a Stille coupling, with vinyl tri-n-butylstannane in the presence of catalytic quantities of benzyl(chloro)-bis(triphenylphosphine)palladium(II) in DMPU (dimethylpropyleneurea) to give 1-(thien-2-yl)propenone of the formula II
which is subsequently converted, by treatment with hydrogen chloride, into 3-chloro-1-(thien-2-yl)propan-1-one of the formula III.1

The chloropropanone III.1 which is obtained in this way is subsequently reduced, using a chiral oxazaborolidine and BH3, to give (S)-3-chloro-1-(thien-2-yl)propan-1-ol of the formula IV.1-S

The alcohol IV.1-S which is obtained in this way is converted, by successively reacting with sodium iodide and then with methylamine, into (S)-3-methylamino-1-(thien-2-yl)propan-1-ol I-S. By subsequently successively reacting with sodium hydride, 1-fluoronaphthalene and hydrogen chloride, duloxetine is obtained in the form of the hydrochloride. In this connection, it is disadvantageous, in the first place, that numerous steps and expensive reagents are required for preparing the chloropropanone intermediate III.1. In the second place, the chloropropanol IV.1-S is isolated when the chloropropanone III.1 is converted into the amino alcohol. However, investigations carried out by the applicant have shown that this chloropropanol is labile and very readily decomposes in a strongly exothermic reaction, something which not only leads to yield losses as regards the amino alcohol but also makes it more difficult to manage the reaction on an industrial scale.
Methods for preparing the 3-chloro-1-(thien-2-yl)propan-1-one, which is described by W. J. Wheeler et al. and which arises as an intermediate during the synthesis of duloxetine, are known from the literature. However, a disadvantage of the known methods from the prior art is that either the chloropropanone III.1 is formed in poor yield or that it is necessary to use reagents which are difficult to handle. Thus, in CR Acad. Sci., Ser. C, 1979, 288 (1), 49-52, A. Etienne et al. describe the preparation of the chloropropanone III.1 by means of the Friedel-Crafts reaction of thiophene with 3-chloropropionyl chloride in the presence of aluminum trichloride, as a Lewis acid catalyst, and in nitromethane as solvent. The chloropropanone III.1 is obtained in a yield of only 7%. The corresponding reaction, as described by Liu et al. in Chirality, 12, 26-29 (2000), in the presence of tin tetrachloride, as the Lewis acid catalyst and benzene, as solvent, also results in an unsatisfactory yield. In Acta Chem. Scand. B 20 (6), 1577-1587 (1966), Meth-Cohn et al. describe the corresponding Friedel-Crafts acylation on thiophene in the presence of iron trichloride or aluminum trichloride, with the chloropropanone III.1 being formed in moderate to good yields. A disadvantage of this method is that carbon disulfide has to be used as solvent.
In Tetrahedron Lett. 44, 2003, 4783-4787, Kamal, G. B. R. Khanna, R. Ramu and T. Krishnaji describe the preparation of the duloxetine precursor (S)-3-hydroxy-3-(thien-2-yl)propanenitrile by means of acetylating thiophene with chloroacetyl chloride, reducing the ketone with sodium borohydride to give the racemic alcohol, replacing the chlorine radical with cyanide and reacting the racemic nitrile alcohol with vinyl acetate in the presence of a Pseudomonas cepacia lipase (immobilized on diatomite), with the lipase selectively catalyzing the esterification of the R enantiomer, such that the desired S enantiomer, which remains unesterified, can be isolated in pure form. Disadvantages in this connection are, on the one hand, the large number of reaction steps which are required and, on the other hand, the loss of half of the nitrile alcohol since the esterified R moiety is not further reacted to give duloxetine.